The present invention relates to pharmaceutical compositions, and particularly pharmaceutical compositions incorporating compounds which are capable of affecting nicotinic chlorinergic receptors. The present invention also relates to methods for treating a wide variety of conditions and disorders, and particularly conditions and disorders associated with dysfunction of the central and automatic nervous systems.
Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al. N. Engl. J.Med. 330:811-815 (1994). Certain of those effects may be related to effects upon neurotransmitter release. See for example, Sjak-shie et al., Brain Res. 624:295 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapier et al., J Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313 (1991) and Vizi, Br. J. Pharmacol. 47:765 (1973). Release of norepinephrine by neurons upon administration of nicotine has been reported by Hall et al., Biochem. Pharmacol. 21:1829 (1972). Release of serotonin by neurons upon administration of nicotine has been reported by Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977). Release of glutamate by neurons upon administration of nicotine has been reported by Toth et al., Neurochem Res. 17:265 (1992). In addition, nicotine reportedly potentiates the pharmacological behavior of certain pharmaceutical compositions used for the treatment of certain CNS disorders. See, Sanberg et al., Pharmacol. Biochem. and Behavior 46:303 (1993); Harsing et al., J. Neurochem. 59:48 (1993) and Hughes, Proceedings from Intl. Symp. Nic. S40 (1994). Furthermore, various other beneficial pharmacological effects of nicotine have been proposed. See, Decina et al., Biol. Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry 21:301 (1988); Pomerleau et al., Addictive Behaviors 9:265 (1984); Onaivi et al., Life Sci. 54(3):193 (1994) and Hamon, Trends in Pharmacol. Res. 15:36.
Various nicotinic compounds have been reported as being useful for treating a wide variety of conditions and disorders. See, for example, Williams et al. DNandP 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1(1):1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1):79-100 (1996), Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET 279:1422 (1996), PCT WO 94/08992, PCT WO 96/31475, and U.S. Pat. No. 5,583,140 to Bencherif et al., U.S. Pat. No. 5,597,919 to Dull et al., and U.S. Pat. No. 5,604,231 to Smith et al. Nicotinic compounds are particularly useful for treating a wide variety of Central Nervous System (CNS) disorders.
CNS disorders are a type of neurological disorder. CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology. CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders. There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors). Several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency and/or a serotonergic deficiency. CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer""s disease), senile dementia (dementia of the Alzheimer""s type), Parkinsonism including Parkinson""s disease, Huntington""s chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette""s syndrome.
Senile dementia of the Alzheimer""s type (SDAT) is a debilitating neurodegenerative disease, mainly afflicting the elderly; characterized by a progressive intellectual and personality decline, as well as a loss of memory, perception, reasoning, orientation and judgment. One feature of the disease is an observed decline in the function of cholinergic systems, and specifically, a severe depletion of cholinergic neurons (i.e., neurons that release acetylcholine, which is believed to be a neurotransmitter involved in learning and memory mechanisms). See, Jones, et al., Intern. J. Neurosci. 50:147 (1990); Perry, Br. Med. Bull. 42:63 (1986); and Sitaram, et al., Science 201:274 (1978). It has been observed that nicotinic acetylcholine receptors, which bind nicotine and other nicotinic agonists with high affinity, are depleted during the progression of SDAT. See, Giacobini, J. Neurosci. Res. 27:548 (1990); and Baron, Neurology 6:1490 (1986). As such, it would seem desirable to provide therapeutic compounds which either directly activate nicotinic receptors in place of acetylcholine or act to minimize the loss of those nicotinic receptors.
Certain attempts have been made to treat SDAT. For example, nicotine has been suggested to possess an ability to activate nicotinic cholinergic receptors upon acute administration, and to elicit an increase in the number of such receptors upon chronic administration to animals. See, Rowell, Adv. Behav. Biol. 31:191 (1987); and Marks, J. Pharmacol. Exp. Ther. 226:817 (1983). It also has been proposed that nicotine can act directly to elicit the release of acetylcholine in brain tissue, to improve cognitive functions, and to enhance attention. See, Rowell, et al., J. Neurochem. 43:1593 (1984); Sherwood, Human Psychopharm. 8:155 (1993); Hodges, et al., Bio. of Nic. Edit. by Lippiello, et al., p. 157 (1991); Sahakian, et al., Br. J. Psych. 154:797 (1989); and U.S. Pat. No. 4,965,074 to Leeson and U.S. Pat. No. 5,242,935 to Lippiello et al. Other methods for treating SDAT have been proposed, including U.S. Pat. No. 5,212,188 to Caldwell et al. and U.S. Pat. No. 5,227,391 to Caldwell et al., European Patent Application No. 588,917 and PCT WO 96/30372. Another proposed treatment for SDAT is COGNEX(copyright), which is a capsule containing tacrine hydrochloride, available from Parke-Davis Division of Warner-Lambert Company, which reportedly preserves existing acetylcholine levels in patients treated therewith.
Parkinson""s disease (PD) is a debilitating neurodegenerative disease, presently of unknown etiology, characterized by tremors and muscular rigidity. A feature of the disease appears to involve the degeneration of dopaminergic neurons (i.e., which secrete dopamine). One symptom of the disease has been observed to be a concomitant loss of nicotinic receptors which are associated with such dopaminergic neurons, and which are believed to modulate the process of dopamine secretion. See, Rinne, et al., Brain Res. 54:167 (1991) and Clark, et al., Br. J. Pharm. 85:827 (1985). It also has been proposed that nicotine can ameliorate the symptoms of PD. See, Smith et al., Rev. Neurosci. 3(1):25 (1992).
Certain attempts have been made to treat PD. One proposed treatment for PD is SINEMET CR(copyright), which is a sustained-release tablet containing a mixture of carbidopa and levodopa, available from The DuPont Merck Pharmaceutical Co. Another proposed treatment for PD is ELDEPRYL(copyright), which is a tablet containing selefiline hydrochloride, available from Somerset Pharmaceuticals, Inc. Another proposed treatment for PD is PARLODEL(copyright), which is a tablet containing bromocriptine mesylate, available from Sandoz Pharmaceuticals Corporation. Another method for treating PD and a variety of other neurodegenerative diseases has been proposed in U.S. Pat. No. 5,210,076 to Berliner et al.
Tourette""s syndrome (TS) is an autosomal dominant neuropsychiatric disorder characterized by a range of neurological and behavioral symptoms. Typical symptoms include (i) the onset of the disorder before the age of 21 years, (ii) multiple motor and phonic tics although not necessarily concurrently, (iii) variance in the clinical phenomenology of the tics, and (iv) occurrence of quasi daily tics throughout a period of time exceeding a year. Motor tics generally include eye blinking, head jerking, shoulder shrugging and facial grimacing; while phonic or vocal tics include throat clearing, sniffling, yelping, tongue clicking and uttering words out of context. The pathophysiology of TS presently is unknown, however it is believed that neurotransmission dysfunction is implicated with the disorder. See, Calderon-Gonzalez et al., Intern. Pediat. 8(2):176 (1993) and OXFORD TEXTBOOK OF MEDICINE, Eds. Weatherall et al., Chapter 21.218 (1987).
It has been proposed that nicotine pharmacology is beneficial in suppressing the symptoms associated with TS. See, Devor et al., The Lancet 8670:1046 (1989); Jarvik, British J. of Addiction 86:571 (1991); McConville et al., Am. J. Psychiatry 148(6):793 (1991); Newhouse et al., Brit. J. Addic. 86:521 (1991); McConville et al., Biol. Psychiatry 31:832 (1992); and Sanberg et al., Proceedings from Intl. Symp. Nic. S39 (1994). It also has been proposed to treat TS using HALDOL(copyright), which is haloperidol available from McNeil Pharmaceutical; CATAPRES(copyright), which is clonidine available from Boehringer Ingelheim Pharmaceuticals, Inc., ORAP(copyright), which is pimozide available from Gate Pharmaceuticals; PROLIXIN(copyright), which is fluphenazine available from Apothecon Division of Bristol-Myers Squibb Co.; and KLONOPIN(copyright), which is clonazepam available from Hoffmann-LaRoche Inc.
Attention deficit disorder (ADD) is a disorder which affects mainly children, although ADD can affect adolescents and adults. See, Vinson, Arch. Fam. Med. 3(5):445 (1994); Hechtman, J. Psychiatry Neurosci. 19(3):193 (1994); Faraone et al., Biol. Psychiatry 35(6):398 (1994) and Malone et al., J. Child Neurol. 9(2):181 (1994). Subjects suffering from the disorder typically have difficulty concentrating, listening, learning and completing tasks; and are restless, fidgety, impulsive and easily distracted. Attention deficit disorder with hyperactivity (ADHD) includes the symptoms of ADD as well as a high level of activity (e.g., restlessness and movement). Attempts to treat ADD have involved administration of DEXEDRINE(copyright), which is a sustained release capsule containing dextroamphetamine sulfate, available from SmithKline Beecham Pharmaceuticals; RITALIN(copyright), which is a tablet containing methylphenidate hydrochloride, available from Ciba Pharmaceutical Company; and CYLERT(copyright), which is a tablet containing premoline, available from Abbott Laboratories. In addition, it has been reported that administration of nicotine to an individual improves that individual""s selective and sustained attention. See, Warburton et al., CHOLINERGIC CONTROL OF COGNITIVE RESOURCES, EUROPSYCHOBIOLOGY, Eds. Mendlewicz, et al., pp. 43-46 (1993) and Levin et al. Psychopharmacology 123:55-63 (1996).
Schizophrenia is characterized by psychotic symptoms including delusions, catatonic behavior and prominent hallucinations, and ultimately results in a profound decline in the psychosocial affect of the subject suffering therefrom. Traditionally, schizophrenia has been treated with KLONOPIN(copyright), which is available as a tablet containing clonezepam, available from Hoffmann-LaRoche Inc.; THORAZINE(copyright), which is available as a tablet containing chlorpromazine, available from SmithKline Beecham Pharmaceuticals; and CLORAZIL(copyright), which is a tablet containing clozapine, available from Sandoz Pharmaceuticals. Such neuroleptics are believed to be effective as a result of interaction thereof with the dopaminergic pathways of the CNS. In addition, a dopaminergic dysfunction possessed by individuals suffering from schizophrenia has been proposed. See, Lieberman et al., Schizophr. Bull. 19:371 (1993) and Glassman, Amer. J. Psychiatry 150:546 (1993). Nicotine has been proposed as being effective in effecting neurotransmitter dysfunction associated with schizophrenia. See, Merriam et al., Psychiatr. Annals 23:171 (1993) and Adler et al., Biol. Psychiatry 32:607 (1992). See also Freedman et al., Proc. Natl. Acad Sci. 94:587-592 (1997).
It would be desirable to provide a useful method for the prevention and treatment of a disorder by administering a nicotinic compound to a patient susceptible to or suffering from such a disorder. It would be highly beneficial to provide individuals suffering from certain disorders (e.g., CNS diseases) with interruption of the symptoms of those disorders by the administration of a pharmaceutical composition containing an active ingredient having nicotinic pharmacology and which has a beneficial effect (e.g., upon the functioning of the CNS), but which does not provide any significant associated side effects (e.g., increased heart rate and blood pressure attendant with interaction of that compound with cardiovascular sites). It would be highly desirable to provide a pharmaceutical composition incorporating a compound which interacts with nicotinic receptors, such as those which have the potential to affect the functioning of the CNS, but which compound does not significantly affect those receptors which have the potential to induce undesirable side effects (e.g., appreciable pressor cardiovascular effects and appreciable activity at skeletal muscle sites).
The present invention relates to aryl substituted olefinic amine compounds. Such compounmds are useful for providing prevention or treatment of central nervous system (CNS) disorders.
In another aspect, the present invention relates to pharmaceutical compositions comprising effective amounts of compounds of the present invention. The pharmaceutical compositions of the present invention each include a compound which is capable of interacting with nicotinic receptor sites of a patient, and thereby acting as a therapeutic agent in the prevention or treatment of a CNS disorder.
In another aspect, the present invention relates to a method for providing prevention or treatment of central nervous system (CNS) disorders. In particular, the method involves administering an aryl substituted olefinic amine compound according to the present invention.
The pharmaceutical compositions of the present invention are useful for the prevention and treatment of CNS disorders. The pharmaceutical compositions provide therapeutic benefit to individuals suffering from certain CNS disorders and exhibiting clinical manifestations of such disorders in that the compounds within those compositions have the potential to (i) exhibit nicotinic pharmacology and affect nicotinic receptors sites in the CNS (e.g., act as a pharmacological agonist to activate nicotinic receptors), and (ii) elicit neurotransmitter secretion, and hence prevent and suppress the symptoms associated with those diseases. In addition, the compounds are expected to have the potential to (i) increase the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects and (iii) not provide appreciable adverse side effects (e.g., significant increases in blood pressure and heart rate, and significant effects upon skeletal muscle). The pharmaceutical compositions of the present invention are believed to be safe and effective with regards to prevention and treatment of CNS disorders.
The compounds of the present invention include compounds of the formula I: 
where X is nitrogen or carbon bonded to a substituent species characterized as having a sigma m value greater than 0, often greater than 0.1, and generally greating than 0.2, and even greater than 0.3; less than 0 and generally less than xe2x88x920.1; or 0; as determined in accordance with Hansch et al., Chem. Rev. 91:165 (1991); n is an integer which is 1, 2, 3, 4, 5, 6, 7, or 8, preferably is 1, 2, or 3, and most preferably is 2 or 3; Exe2x80x2 represents hydrogen or lower alkyl (e.g., straight chain or branched alkyl including C1-C8, preferably C1-C5, such as methyl, ethyl, or isopropyl) or halo substituted lower alkyl (e.g., straight chain or branched alkyl including C1-C8, preferably C1-C5, such as trifluoromethyl or trichloromethyl), but preferably is H; Exe2x80x3 represents lower alkyl (e.g., straight chain or branched alkyl including C1-C8, preferably C1-C5, such as methyl, ethyl, or isopropyl) or halo substituted lower alkyl (e.g., straight chain or branched alkyl including C1-C8, preferably C1-C5, such as trifluoromethyl or trichloromethyl); Zxe2x80x2 and Zxe2x80x3 individually represent hydrogen or lower alkyl (e.g., straight chain or branched alkyl including C1-C8, preferably C1-C5, such as methyl, ethyl, or isopropyl), and preferably at least one of Zxe2x80x2 and Zxe2x80x3 is hydrogen, and most preferably Zxe2x80x2 is hydrogen and Zxe2x80x3 is methyl; alternatively Zxe2x80x2 is hydrogen and Zxe2x80x3 represents a ring structure (cycloalkyl or aromatic), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, quinuclidinyl, pyridinyl, quinolinyl, pyrimidinyl, phenyl, benzyl (where any of the foregoing can be suitably substiuted with at least one substituent group, such as alkyl, halo, or amino substituents); alternatively Zxe2x80x2, Zxe2x80x3, and the associated nitrogen atom can form a ring structure such as aziridinyl, azetidinyl, pyrollidinyl, piperidinyl, piperazinyl, or morpholinyl; A, Axe2x80x2 and Axe2x80x3 individually represent hydrogen, halo (e.g., F, Cl, Br, or I), alkyl (e.g., lower straight chain or branched C1-8 alkyl, but preferably methyl or ethyl), or NXxe2x80x3Xxe2x80x2xe2x80x3 where Xxe2x80x3 and Xxe2x80x2xe2x80x3 are individually hydrogen or lower alkyl, including C1-C8, preferably C1-C5 alkyl; m is 0 or 1, preferably 0; p is 0 or 1, preferably 0; the wavy line in the structure represents a cis (Z) or trans (E) form of the compound. When m or p is 0, Exe2x80x3 is not present and H fills the valence of the carbon on which Exe2x80x3 is positioned. More specifically, X includes N, Cxe2x80x94H, Cxe2x80x94F, Cxe2x80x94Cl, Cxe2x80x94Br, Cxe2x80x94I, Cxe2x80x94Rxe2x80x2, Cxe2x80x94NRxe2x80x2Rxe2x80x3, Cxe2x80x94CF3, Cxe2x80x94OH, Cxe2x80x94CN, Cxe2x80x94NO2, Cxe2x80x94C2Rxe2x80x2, Cxe2x80x94SH, Cxe2x80x94SCH3, Cxe2x80x94N3, Cxe2x80x94SO2CH3, Cxe2x80x94ORxe2x80x2, Cxe2x80x94SRxe2x80x2, Cxe2x80x94C(xe2x95x90O)NRxe2x80x2Rxe2x80x3, Cxe2x80x94NRxe2x80x2C(xe2x95x90O)Rxe2x80x2, Cxe2x80x94C(xe2x95x90O)Rxe2x80x2, Cxe2x80x94C(xe2x95x90O)ORxe2x80x2, C(CH2)qORxe2x80x2, Cxe2x80x94OC(xe2x95x90O)Rxe2x80x2, COC(xe2x95x90O)NRxe2x80x2Rxe2x80x3 and Cxe2x80x94NRxe2x80x2C(xe2x95x90O)ORxe2x80x2 where Rxe2x80x2 and Rxe2x80x3 are individually hydrogen or lower alkyl (e.g., C1-C10 alkyl, preferably C1-C5 alkyl, and more preferably methyl, ethyl, isopropyl or isobutyl), an aromatic group-containing species or a substituted aromatic group-containing species, and q is an integer from 1 to 6. Rxe2x80x2 and Rxe2x80x3 can be straight chain or branched alkyl, or Rxe2x80x2 and Rxe2x80x3 can form a cycloalkyl funtionality (e.g., cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and quinuclidinyl). Representative aromatic group-containing species include pyridinyl, quinolinyl, pyrimidinyl, phenyl, and benzyl (where any of the foregoing can be suitably substituted with at least one substituent group, such as alkyl, halo, or amino substituents). Other representative aromatic ring systems are set forth in Gibson et al., J. Med. Chem. 39:4065 (1996). When X represents a carbon atom bonded to a substituent species, that substituent species often has a sigma m value which is between about xe2x80x940.3 and about 0.75, and frequently between about xe2x88x920.25 and about 0.6. In certain circumstances the substituent species is characterized as having a sigma m value not equal to 0. In addition, it is highly preferred that A is hydrogen, it is preferred that Axe2x80x2 is hydrogen, and normally Axe2x80x3 is hydrogen. Generally, both A and Axe2x80x2 are hydrogen; sometimes A and Axe2x80x2 are hydrogen, and Axe2x80x3 is amino, methyl or ethyl; and often A, Axe2x80x2 and Axe2x80x3 are all hydrogen. Depending upon the identity and positioning of each individual Exe2x80x2, certain compounds can be optically active. Typically, the values of each of m and p, and the selection of Exe2x80x2, are such that up to about 4, and frequently up to 3, of the substituents designated as Exe2x80x2 and Exe2x80x3 are non-hydrogen substituents (i.e., substituents such as lower alkyl or halo-substituted lower alkyl).
Of particularly interest are compounds of Formula I where n, m, p, X, A, Axe2x80x2, Axe2x80x3, Exe2x80x2, Exe2x80x3, Zxe2x80x2, and Zxe2x80x3 are as defined hereinbefore, and those compounds can have the cis (Z) or trans (E) form. For such compounds of particular interest, X most preferably is nitrogen or carbon bonded to a substituent species characterized as having a sigma m value greater than 0, often greater than 0.1, generally greater than 0.2, and even greater than 0.3; less than 0 and generally less than xe2x88x920.1; or 0. More specifically, the compounds of particular interest are those compounds wherein X is CH, Cxe2x80x94Br, C(CH2)qORxe2x80x2, where Rxe2x80x2 is an aromatic ring, particularly phenyl; Cxe2x80x94Oxe2x80x94Rxe2x80x2 where Rxe2x80x2 is an aromatic ring, particularly phenyl; Cxe2x80x94Oxe2x80x94Rxe2x80x2 where Rxe2x80x2 is an alkyl particularly isopropyl or ethyl; Cxe2x80x94CORxe2x80x2 where Rxe2x80x2 is methyl.
One representative compound is (E)-N-methyl-4-[3-(5-benzyloxypyridin)yl]-3-buten-1-amine for which X is Cxe2x80x94Oxe2x80x94CH2Ar, where Ar is phenyl, Exe2x80x2 is H, n is 2, m is 0, p is 0, A, Axe2x80x2, Axe2x80x3, and Zxe2x80x2 are each H, and Zxe2x80x3 is methyl. Another representative compound is (E)-4-[3-(5-bromopyrdin)yl]-3-buten-1-amine for which X is Cxe2x80x94Br, Exe2x80x2 is H, n is 2, m is 0, p is 0, and A, Axe2x80x2, Axe2x80x3, Zxe2x80x2 and Zxe2x80x3 are each H. Another representative compound is (E)-N-methyl-4-[3-(5-phenoxypyridin)yl]-3-buten-1-amine for which X is Cxe2x80x94Oxe2x80x94Ar where Ar is phenyl, Exe2x80x2 is H, n is 2, m is 0, p is 0, A, Axe2x80x2, Axe2x80x3, and Zxe2x80x2 are each H, and Zxe2x80x3 is methyl. Another representative compound is (E)-N-methyl-4-[3-(5-isopropoxypyridin)yl]-3-buten-1-amine for which X is Cxe2x80x94Oxe2x80x94Rxe2x80x2 where Rxe2x80x2 is isopropyl, Exe2x80x2 is H, n is 2, m is 0, p is 0, A, Axe2x80x2, Axe2x80x3, and Zxe2x80x2 are each H, and Zxe2x80x3 is methyl. Another representative compound is (E)-N-methyl-4-[3-(5-methoxymethylpyridin)yl-3-buten-1-amine for which X is Cxe2x80x94CH2xe2x80x94Oxe2x80x94CH3, Exe2x80x2 is H, n is 2, m is 0, p is 0, A, Axe2x80x2, Axe2x80x3, and Zxe2x80x2 are each H, and Zxe2x80x3 is methyl. Another representative compound is (E)-N-methyl-4-[3-(5-phenylpyridin)yl]-3-buten-1-amine for which X is Cxe2x80x94Rxe2x80x2 where Rxe2x80x2 is phenyl, Exe2x80x2 is H, n is 2, Exe2x80x3 is H, m is 0, p is 0, A, Axe2x80x2, Axe2x80x3, and Zxe2x80x2 are each H, and Zxe2x80x3 is methyl. Another representative compound is (E)-4-(3-pyridinyl)-3-buten-1-amine for which X is CH2, Exe2x80x2 is H, n is 2, m is 0, p is 0, and A, Axe2x80x2, Axe2x80x3, Zxe2x80x2 and Zxe2x80x3 are each H. Another representative compound is (E)-N-methyl-4-[3-(5-ethoxypyridin)yl]-3-buten-1-amine for which X is Cxe2x80x94Oxe2x80x94Rxe2x80x2 where Rxe2x80x2 is ethyl, Exe2x80x2 is H, n is 2, m is 0, p is 0, A, Axe2x80x2, Axe2x80x3, Zxe2x80x2 are each H, and Zxe2x80x3 is methyl.
Another representative compound is (E)-N-methyl-4-[3-5-(ethylthiopyridinyl)]-3-buten-1-amine for which X is Cxe2x80x94Sxe2x80x94C2H5, Exe2x80x2 is H, n is 2, m is 0, p is 0, and A, Axe2x80x2, Axe2x80x3 and Zxe2x80x2 are each H and Zxe2x80x3 is methyl. Another representative compound is (E)-N-methyl-4-[3-5-acetamidopyridinyl]-3-buten-1-amine for which X is Cxe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH3, Exe2x80x2 is H, n is 2, m is 0, p is 0, and A, Axe2x80x2, Axe2x80x3 and Zxe2x80x2 are each H and Zxe2x80x3 is methyl. Another representative compound is (E)-N-methyl-4-[3-5-carbamoyl-pyridinyl]-3-buten-1-amine for which X is Cxe2x80x94C(xe2x95x90O)xe2x80x94NH2, Exe2x80x2 is H, n is 2, m is 0, p is 0, and A, Axe2x80x2, Axe2x80x3 and Zxe2x80x2 are each H and Zxe2x80x3 is methyl.
The manner in which aryl substituted olefinic amine compounds of the present invention are provided can vary. (E)-metanicotine can be prepared using the techniques set forth by Lxc3x6ffler et al., Chem. Ber. 42:3431 (1909) and Laforge, J.A.C.S. 50:2477 (1928). Certain novel 6-substituted metanicotine-type compounds can be prepared from the corresponding 6-substituted nicotine-type compounds using the general methods of Acheson et al., J. Chem. Soc., Perkin Trans. 1 2:579 (1980). The requisite precursors for such compounds, i.e., 6-substituted nicotine-type compounds, can be synthesized from 6-substituted nicotinic acid esters using the general methods disclosed by Rondahl, Acta Pharm. Suec. 14:113 (1977). Preparation of certain 5-substituted metanicotine-type compounds can be accomplished from the corresponding 5-substituted nicotine-type compounds using the general method taught by Acheson et al., J. Chem. Soc., Perkin Trans. 1 2:579 (1980). The 5-halo nicotine-type compounds and the 5-amino nicotine-type compounds can be prepared using the general procedures disclosed by Rondahl, Act. Pharm. Suec. 14:113 (1977). The 5-trifluoromethyl nicotine-type compounds can be prepared using the techniques and materials set forth in Ashimori et al., Chem. Pharm. Bull. 38(9):2446 (1990) and Rondahl, Acta Pharm. Suec. 14:113 (1977). Certain metanicotine-type compounds (e.g., 3-(5-phenylpyridin)yl-3-alkene-amine type compounds) can be prepared using the types of synthetic methodologies set forth in Miyaura et al., Synth. Commun. 11:513 (1981) and U.S. Pat. No. 5,409,920 to Guthikonda et al. Furthermore, preparation of certain metanicotine-type compounds can be accomplished using a palladium catalyzed coupling reaction of an aromatic halide and a terminal olefin containing a protected amine substituent, removal of the protective group to obtain a primary amine, and optional alkylation to provide a secondary or tertiary amine. In particular, certain metanicotine-type compounds can be prepared by subjecting a 3-halo substituted, 5-substituted pyridine compound or a 5-halo substituted pyrimidine compound to a palladium catalyzed coupling reaction using an olefin possessing a protected amine functionality (e.g., an olefin provided by the reaction of a phthalimide salt with 3-halo-1-propene, 4-halo-1-butene, 5-halo-1-pentene or 6-halo-1-hexene). See, Frank et al., J. Org Chem. 43(15):2947 (1978) and Malek et al., J. Org. Chem. 47:5395 (1982). Alternatively, certain metanicotine-type compounds can be prepared by coupling an N-protected, modified amino acid residue, such as 4-(N-methyl-N-tert-butyloxycarbonyl)amino-butyric acid methyl ester, with an aryl lithium compound, as can be derived from a suitable aryl halide and butyl lithium. The resulting N-protected aryl ketone is then chemically reduced to the corresponding alcohol, converted to the alkyl halide, and subsequently dehydrohalogenated to introduce the olefin functionality. Removal of the N-protecting group affords the desired metanicotine-type compound.
There are a number of different methods for providing (Z)-metanicotine-type compounds. In one method, (Z)-metanicotine-type compounds can be synthesized from nicotine as a mixture of the E and Z isomers; and the (Z)-metanicotine-type compounds can then be separated by chromatography using the types of techniques disclosed by Sprouse et al., Abstracts of Papers, p. 32, Coresta/TCRC Joint Conference (1972). In another method, (Z)-metanicotine can be prepared by the controlled hydrogenation of the corresponding acetylenic compound (e.g., N-methyl-4-(3-pyridinyl)-3-butynylamine). For example, certain 5-substituted (Z)-metanicotine-type compounds and certain 6-substituted (Z)-metanicotine-type compounds can be prepared from 5-substituted-3-pyridinecarboxaldehydes and 6-substituted-3-pyridinecarboxaldehydes, respectively.
Representative compounds of the present invention, representative starting materials, and methods of synthesizing representative compounds and suitable salts thereof are set forth in U.S. Pat. No. 5,597,919 to Dull et al.; U.S. patent application Sers. No. 08/631,762; 08/635,165; and PCT No. WO 96/31475.
One representative compound, (E)-N-methyl-4-(3-[5-(ethylthio)pyridinyl])-3-buten-1-amine is prepared from N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine and 3-bromo-5-(ethylthio)pyridine using the techniques set forth in W. C. Frank, et al., J. Org. Chem. 43(15):2947 (1978), and the tert-butoxy carbonyl protecting group is subsequently removed. Specifically, N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine is prepared by (i) reacting 4-bromo-1-butene at 0.035 mole scale with a ten fold excess of condensed methylamine in N,N-dimethylformamide solvent in the presence of potassium carbonate to provide a 97% yield of N-mehtyl-3-buten-1-amine; (ii) the amine thus prepared is reacted at 0.030 mole scale with one equivalent of di-tert-butyldicarbonate in tetrahydrofuran to give N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine in 68% yield. The 3-bromo-5-(ethylthio)pyridine is produced by the reaction of sodium ethanethiolate on 3,5-dibromopyridine in N,N-dimethylformamide in 86% yield. N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine and 3-bromo-5-(ethylthio)pyridine are reacted using the Heck reaction on a 1.6 mmole scale in 2:1 acetonitrile:triethylamine using a catalyst consistingof one mole percent palladium acetate and four mole percent tri-o-tolylphosphine. N-methyl-N-(tert-butoxycarbonyl)-4-(3-[5-(ethylthio)pyridinyl])-3-buten-1-amine is obtained in 59% yield. Deprotection of the product may then be accomplished by 1:1 6N hydrochloric acid:tetrahdyrofuran.
Other representative compounds include (E)-N-methyl-4-[3-(5-acetamidopyridinyl)]-3-buten-1-amine and (E)-N-methyl-4-[3-(5-carbamoylpyridinyl)]-3-buten-1-amine. These compounds may be produced according to the techniques set forth in C. V. Greco et al., J. Heterocyclic Chem. 7(4):761 (1970). More specifically, the commercially available starting material, 5-bromonicotinic acid is converted to both 5-bromonicotinamide and 3-amino-5-bromopyridine. The 3-amino-5-bromopyridine can be acylated with acetic anhydride to give 3-acetamido-5-bromopyridine. 3-Acetamido-5-bromopyridine may then be reacted with N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine (prepared according to the preceeding techniques) using the Heck reaction described hereinabove and set forth in W. C. Frank et al., J. Org. Chem. 43(15):2947 (1978). The reaction gives (E)-N-methyl-N-(tert-butoxycarbonyl)-4-[3-(5-acetamidopyridinyl)]-3-buten-1-amine. The Heck reaction of 5-bromonicotinic acid with N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine gives (E)-N-methyl-N-(tert-butoxycarbonyl)-4-[3-(5-carbamoylpyridinyl)]-3-buten-1-amine. The treatment of either product with aqueous acid effects the removal of the tert-butoxycarbonyl groups from these compounds, giving the 5-acetamido and 5-carbamoyl substituted metanicotinic compounds respectively.
The present invention relates to a method for providing prevention of a CNS disorder to a subject susceptible to such a disorder, and for providing treatment to a subject suffering from a CNS disorder. In particular, the method comprises administering to a patient an amount of a compound effective for providing some degree of prevention of the progression of the CNS disorder (i.e., provide protective effects), amelioration of the symptoms of the CNS disorder, and amelioration of the reoccurrence of the CNS disorder. The method involves administering an effective amount of a compound selected from the general formulae which are set forth hereinbefore. The present invention relates to a pharmaceutical composition incorporating a compound selected from the general formulae which are set forth hereinbefore. The compounds normally are not optically active. However, certain compounds can possess substituent groups of a character so that those compounds possess optical activity. Optically active compounds can be employed as racemic mixtures or as enantiomers. The compounds can be employed in a free base form or in a salt form (e.g., as pharmaceutically acceptable salts). Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,Nxe2x80x2-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt. The salts may be in some cases hydrates or ethanol solvates.
CNS disorders which can be treated in accordance with the present invention include presenile dementia (early onset Alzheimer""s disease), senile dementia (dementia of the Alzheimer""s type), Parkinsonism including Parkinson""s disease, Huntington""s chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette""s syndrome.
The pharmaceutical composition also can include various other components as additives or adjuncts. Exemplary pharmaceutically acceptable components or adjuncts which are employed in relevant circumstances include antioxidants, free radical scavenging agents, peptides, growth factors, antibiotics, bacteriostatic agents, immunosuppressives, anticoagulants, buffering agents, anti-inflammatory agents, anti-pyretics, time release binders, anaesthetics, steroids and corticosteroids. Such components can provide additional therapeutic benefit, act to affect the therapeutic action of the pharmaceutical composition, or act towards preventing any potential side effects which may be posed as a result of administration of the pharmaceutical composition. In certain circumstances, a compound of the present invention can be employed as part of a pharmaceutical composition with other compounds intended to prevent or treat a particular CNS disorder.
The manner in which the compounds are administered can vary. The compounds can be administered by inhalation (e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Pat. No. 4,922,901 to Brooks et al.); topically (e.g., in lotion form); orally (e.g., in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within a solid carrier); intravenously (e.g., within a dextrose or saline solution); as an infusion or injection (e.g., as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids); or transdermally (e.g., using a transdermal patch). Although it is possible to administer the compounds in the form of a bulk active chemical, it is preferred to present each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration. Exemplary methods for administering such compounds will be apparent to the skilled artisan. For example, the compounds can be administered in the form of a tablet, a hard gelatin capsule or as a time release capsule. As another example, the compounds can be delivered transdermally using the types of patch technologies available from Ciba-Geigy Corporation and Alza Corporation. The administration of the pharmaceutical compositions of the present invention can be intermittent, or at a gradual, continuous, constant or controlled rate to a warm-blooded animal, such as a human being. In addition, the time of day and the number of times per day that the pharmaceutical formulation is administered can vary. Administration preferably is such that the active ingredients of the pharmaceutical formulation interact with receptor sites within the body of the subject that effect the functioning of the CNS.
The dose of the compound is that amount effective to prevent occurrence of the symptoms of the condition being prevented, or to treat some symptoms of the condition from which the patient suffers. By xe2x80x9ceffective amountxe2x80x9d, xe2x80x9ctherapeutic amountxe2x80x9d or xe2x80x9ceffective dosexe2x80x9d is meant an amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the CNS disorder. Thus, an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject, and to elicit neuropharmacological effects (e.g., elicit neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder). Prevention of the disorder is manifested by a prolonging or delaying of the onset of the symptoms of the condition. Treatment of the condition is manifested by a decrease in the symptoms associated with the disorder or an amelioration of the reoccurrence of the symptoms of the disorder.
The effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms experienced by the patient, and the manner in which the pharmaceutical composition is administered. For human patients, the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1, often at least about 10, and frequently at least about 25 mg/24 hr./patient. For human patients, the effective dose of typical compounds requires administering the compound which generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 mg/24 hr./patient. In addition, administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 ng/ml, and frequently does not exceed 100 ng/ml.
The compounds useful according to the method of the present invention have the ability to pass across the blood-brain barrier of the patient. As such, such compounds have the ability to enter the central nervous system of the patient. The log P values of typical compounds useful in carrying out the present invention generally are greater than xe2x88x920.5, often are greater than about 0, and frequently are greater than about 0.5. The log P values of such typical compounds generally are less than about 3.5, often are less than about 3.0, and frequently are less than about 2.5. Log P values provide a measure of the ability of a compound to pass across a diffusion barrier, such as a biological membrane. See, Hansch, et al., J. Med Chem. 11:1 (1968).
The compounds useful according to the method of the present invention have the ability to interact with certain nicotinic cholinergic receptors in the brain of the patient. As such these compound have the ability to express nicotinic pharmacology, and in particular, to act as nicotinic agonists. The receptor binding constants of typical compounds useful in carrying out the present invention generally exceed about 1 nM, often exceed about 5 nM, and frequently exceed about 10 nM. The receptor binding constants of such typical compounds generally are less than about 1000 nM, often are less than about 500 nM, frequently are less than about 200 nM, and even less than 100 nM. Receptor binding constants provide a measure of the ability of the compound to bind to relevant receptor sites of certain cells of the patient. See, Cheng, et al., Biochem. Pharmacol. 22:3099 (1973).
The compounds useful according to the method of the present invention have the ability to demonstrate a nicotinic pharmacology by effectively eliciting neurotransmitter secretion from nerve ending preparations (i.e., synaptosomes). As such, these compounds have the ability to cause relevant neurons to release or secrete acetylcholine, dopamine, and other neurotransmitters. Generally, the compounds useful in carrying out the present invention provide for the secretion of dopamine in amounts of at least about percent, often at least about 25 percent, frequently at least about 50 percent and even greater than 75 percent, of that elicited by an equal molar amount of (S)-(xe2x88x92)-nicotine. Certain compounds of the present invention can provide secretion of dopamine in an amount which can exceed that elicited by an equal molar amount of (S)-(xe2x88x92)-nicotine.
The compounds of the present invention, when employed in effective amounts in accordance with the method of the present invention, lack the ability to elicit activation of nicotinic receptors of human muscle to any significant degree. In that regard, the compounds of the present invention demonstrate poor ability to cause isotopic rubidium ion flux through nicotinic receptors in cell preparations derived from muscle preparations. Thus, such compounds exhibit receptor activation constants or EC50 values (i.e., which provide a measure of the concentration of compound needed to activate half of the relevant receptor sites of the skeletal muscle of a patient) which are relatively high. Generally, typical compounds useful in carrying out the present invention activate isotopic rubidium ion flux by less than 20 percent, often by less than 15 percent, and frequently by less than 10 percent, of that elicited by an equal molar amount of (S)-(xe2x88x92)-nicotine.
The compounds of the present invention, when employed in effective amounts in accordance with the method of the present invention, are selective to certain relevant nicotinic receptors, but do not cause significant activation of receptors associated with undesirable side effects. By this is meant that a particular dose of compound resulting in prevention and/or treatment of a CNS disorder is essentially ineffective in eliciting activation of certain ganglionic-type nicotinic receptors. This selectivity of the compounds of the present invention against those receptors responsible for cardiovascular side effects is demonstrated by a lack of the ability of those compounds to activate nicotinic function of adrenal chromaffin tissue. As such, the compounds of the present invention have poor ability to cause isotopic rubidium ion flux through nicotinic receptors in cell preparations derived from the adrenal gland. Generally, the compounds useful in the present invention activate isotopic rubidium ion flux by less than 25 percent, often by less than 15 percent, frequently by less than 10 percent, and even essentially 0 percent, of that elicited by an equal molar amount of (S)-(xe2x88x92)-nicotine.
Compounds of the present invention, when employed in effective amounts in accordance with the method of the present invention, are effective towards providing some degree of prevention of CNS disorders amelioration of the symptoms of such disorders, and amelioration to some degree of the reoccurrence of such disorders. However, such effective amounts of those compounds are not sufficient to elicit any appreciable side effects, as demonstrated by increased effects relating to the cardiovascular system, and effects to skeletal muscle. As such, administration of compounds of the present invention provides a therapeutic window in which treatment of CNS disorders is provided, and side effects are avoided. That is, an effective dose of a compound of the present invention is sufficient to provide the desired effects upon the CNS, but is insufficient (i.e., is not at a high enough level) to provide undesirable side effects. Preferably, effective administration of a compound of the present invention resulting in treatment of a CNS disorder occurs upon administration of less than 1/5, often less than 1/10, and frequently less than 1/15, that amount sufficient to cause any side effects to a significant degree.